Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness.
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness.
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DOI：
10.1038/s41398-021-01256-3
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发表时间：
2021-02-19
影响因子：
6.8
通讯作者：
Kirsty Millar J
中科院分区：
文献类型：
--
作者：
Bonneau M;Sullivan STO;Gonzalez-Lozano MA;Baxter P;Gautier P;Marchisella E;Hardingham NR;Chesters RA;Torrance H;Howard DM;Jansen MA;McMillan M;Singh Y;Didier M;Koopmans F;Semple CA;McIntosh AM;Volkmer H;Loos M;Fox K;Hardingham GE;Vernon AC;Porteous DJ;Smit AB;Price DJ;Kirsty Millar J
直接破坏DISC 1的平衡t（1;11）易位与精神分裂症和情感障碍有关。我们以前表明，突变小鼠，命名为Der 1，概括了DISC 1表达后的易位的影响。在这里，Der 1小鼠脑组织的RNAseq分析发现了与先前通过诱导多能干细胞途径从人t（1;11）易位携带者产生的神经元培养物中相同的基因和分子途径的失调的富集。因此，DISC 1破坏显然占t（1;11）易位效应的很大比例。突变小鼠的RNAseq和通路分析预测了多个Der 1诱导的改变，这些改变聚集在突触功能和可塑性上。突触体蛋白质组学证实Der 1突变影响突触组成，电生理学发现海马神经元中AMPA：NMDA比率降低，表明兴奋性信号传导改变。此外，海马小白蛋白阳性中间神经元密度增加，这表明Der 1突变影响神经元回路的抑制控制。这些表型预测神经传递在许多水平上受到人类t（1;11）易位携带者DISC 1破坏的影响。值得注意的是，大规模遗传学研究发现，精神分裂症、抑郁症和双相情感障碍的相关基因在Der 1失调基因中富集，就像我们之前观察到的t（1;11）易位携带者衍生的神经元一样。此外，RNAseq分析预测，Der 1突变主要针对细胞类型的子集，锥体神经元和中间神经元，这些细胞类型以前被证明易受常见精神分裂症相关遗传变异的影响。总之，DISC 1中断的t（1;11）易位可能有助于易位携带者的精神疾病，通过共同影响的途径和过程中的神经传递。
A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.
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影响因子：
3.7
作者：
Hattori T;Shimizu S;Koyama Y;Emoto H;Matsumoto Y;Kumamoto N;Yamada K;Takamura H;Matsuzaki S;Katayama T;Tohyama M;Ito A
通讯作者：
Ito A
影响因子：
12.7
作者：
Chapuis J;Flaig A;Grenier-Boley B;Eysert F;Pottiez V;Deloison G;Vandeputte A;Ayral AM;Mendes T;Desai S;Goate AM;Kauwe JSK;Leroux F;Herledan A;Demiautte F;Bauer C;Checler F;Petersen RC;Blennow K;Zetterberg H;Minthon L;Van Deerlin VM;Lee VM;Shaw LM;Trojanowski JQ;Albert M;Moghekar A;O'Brien R;Peskind ER;Malmanche N;Schellenberg GD;Dourlen P;Song OR;Cruchaga C;Amouyel P;Deprez B;Brodin P;Lambert JC;ADGC, Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
ADGC, Alzheimer’s Disease Neuroimaging Initiative
影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
关于精神疾病的新看法：超越胶水的神经胶质参与。
影响因子：
5.3
作者：
Elsayed M;Magistretti PJ
通讯作者：
Magistretti PJ
影响因子：
9.8
作者：
Blackwood, DHR;Fordyce, A;Muir, WJ
通讯作者：
Muir, WJ